Diagnostic value of ultrasound elastography in triple negative breast cancer: A meta-analysis

Background: The purpose of this study was to determine the value of ultrasound elastic imaging (UE) in the differential diagnosis of the 3 negative breast cancer (TNBC) and non-TNBC. Methods: We searched the PubMed, Cochrane Library, and CBM databases from inception to July 20, 2022 and used STATA version 14.0 and Meta-Disc version 1.4 software. We computed summary statistics for sensitivity (Sen), specificity, positive and negative likelihood ratio (LR+/LR−), diagnostic odds ratio, and summary receiver operating characteristic curves. Cochran Q-statistic and I2 test were used to assess potential heterogeneity between studies. Sen analysis was carried out to evaluate the effect of a single study on overall estimation. We also conducted a meta regression analysis to investigate potential sources of heterogeneity. Results: Nine studies that fulfilled all the criteria for acceptance were incorporated into the meta-analysis. TNBC 317 and non-TNBC 1055 cases were evaluated. All breast tumors were histologically confirmed. The pooled Sen was 0.78 (95% confidence interval [CI] = 0.58–0.90); the pooled specificity was 0.86 (95%CI = 0.78–0.91). The pooled LR+ was 5.46 (95%CI = 3.07–9.73); the pooled negative LR− was 0.26 (95%CI = 0.12–0.55). The pooled diagnostic odds ratio of UE was 21.00 (95% CI = 6.14–71.78). The area under the summary receiver operating characteristic curve was 0.89 (SE = 0.0378). No evidence was found to reveal bias (t = 0.10, P = .92). Conclusion: Our meta-analysis showed that UE could have high diagnostic accuracy in distinguishing TNBC and non-TNBC.


Introduction
In recent years, the incidence rate of breast cancer has increased year by year and has a younger trend, seriously endangering the health of women. [1] Triple negative breast cancers, as a special subtype of breast cancer, is characterized by a lack expression of estrogen receptors, progesterone receptors and human epidermal growth factor receptor-2. [2] Triple negative breast cancer (TNBC) tends to occur in young women and has the characteristics of high invasion, high recurrence rate, high mortality and insensitivity to endocrine therapy and targeted therapy. [3] However, it is sensitive to preoperative neoadjuvant chemotherapy. [4] Therefore, early identification of TNBC is particularly important for formulating a reasonable treatment plan.
At present, the imaging methods used for breast lesions mainly include aluminum target radiography, ultrasound and magnetic resonance imaging. Due to the long examination time, high cost, complex procedures and other reasons, and MRI examination is not the preferred examination method. [5] It is mainly used for the screening of high-risk groups with breast cancer or the preoperative and postoperative condition evaluation of breast conserving surgery for patients with breast cancer. [6] For the fatty breast of postmenopausal women, molybdenum target can clearly show each layer of tissue and micro calcification. However, for patients with dense breast (generally young women), the effect of distinguishing breast lesions is poor, and the key target is radioactive, which is not suitable for short-term reexamination. [7] Ultrasound has many advantages, such as high spatial resolution, real-time imaging, no radiation and low cost, which has become the most common method of breast examination. [8] However, ultrasound diagnostic capability is impaired because TNBC lacks in the typical malignant ultrasound features of breast cancer. [9] As a new technology, ultrasound elastography (UE) is widely used in clinics. It mainly reflects the histological changes of the Medicine tumor by judging the tissue elastic hardness of the lesion area, so as to judge its biological behavior characteristics. [10] Previous studies have revealed that analyzing the hardness features of breast tumors can provide reliable information for TNBC diagnosis. [11] However, the results were different from clinical trials, and there was no meta-analysis and guidance of this technical diagnosis TNBC. The purpose of this study was to analyze the diagnostic value of UE in TNBC and non-TNBC differential diagnosis by meta-analysis.

Ethics and dissemination
Since this study is based on the data of the published literature, ethical documents were not obtained. We would like to announce this research to the company review periodical. This research has not been registered and the plan has not been created.

Literature search
From the establishment to July 20, 2022, PubMed, Cochrane Library and CBM database were searched using the following keywords: ["triple-negative breast cancer" or "triple-negative breast neoplasm" or "triple-negative breast tumor"] and ["ultrasound elastography" or "shear wave elastography" or "virtual touch tissue imaging quantification"]. A manual search for identifying other potential articles was also made.

Selection criteria
Each study met the following criteria: the study design must be a clinical cohort study or diagnostic test; this study must be related to the accuracy of TNBC diagnosis by UE; all breast tumors were histologically proven; and published data in the 4fold (2 × 2) tables must be sufficient. If this study did not meet all selection criteria, it was excluded. If the author announces several studies using the same theme, it contains the most sample volumes.

Data extraction
The 2 researchers extracted the relevant data systematically from all the integrated studies using the standard table. The researchers collected the following data: first author surname, publication year, language of publication, study design, sample size, number of lesions, source of the subjects, "gold standard." True positives (TP), true negatives (TN), false positives (FP), and false negatives (FN) in the 4fold (2 × 2) tables were also collected.

Quality assessment
Two researchers evaluated their methodological quality with a quality assessment of studies of diagnostic accuracy studies (QUADAS) tool. [12] The QUADAS standard contains 14 evaluation items. The scores for each item are "yes" (2), "no" (0), or "unknown" (1). The range of QUADAS is 0 to 28, and the score ≧ 22 indicates good quality.

Statistical analysis
STATA version 14.0 (Stata Corp, College Station, TX) and Meta-Disc version 1.4 (Universidad Complutense, Madrid, Spain) software were used for meta-analysis. We calculated the pooled summary statistics for sensitivity (Sen), specificity (Spe), positive and negative likelihood ratio (LR+/LR−), and diagnostic odds ratio (DOR) with 95%confidence intervals (CIs). The post-test probabilities were calculated by the LR + and LR − and plotted on a Fagan nomogram. A summary receiver operating characteristic curve and corresponding area under the curve (AUC) were obtained. The threshold effect was evaluated using Spearman correlation coefficients. Cochran Q-statistic and I 2 test were used to evaluate potential heterogeneity between studies. If significant heterogeneity was detected (Q test P < .05, or I test > 50%), a random-effects model or fixed-effects model was used. We also conducted a meta-regression analysis to investigate the potential sources of heterogeneity. Sen analysis was carried out to evaluate the effect of a single study on overall estimation. The announcement deviation was investigated using Begger funnel plots and Egger linear regression tests.

Characteristics of included studies
Initially, the search keywords were used to identify 51 articles. We reviewed the titles and abstracts of all articles and excluded 32 articles; full texts and data integrity were also reviewed, and 10 were further excluded. Finally, 9 studies that met all inclusion criteria were included in this meta-analysis. [13][14][15][16][17][18][19][20][21] Figure 1 shows a procedure for selecting an article satisfying the conditions. The Table 1 Baseline characteristics and methodological quality of all included studies.        Table 1.
All the QUADAS scores incorporated in the study were ≧ 22.

Quantitative data synthesis
The random effect model was used because there was an obvious heterogeneity between the studies. Although sensitivity analysis was carried out, there was no item to give clear interference to the meta-analysis result (Fig. 2). The pooled Sen was 0.78 (95%CI = 0.58-0.90); the pooled Spe was 0.86 (95%CI = 0.78-0.91). (Fig. 3). There was no significant correlation (R = 0.293, P = .444) between the sensitivity and specificity, indicating no threshold effect. The pooled LR + was 5.46 (95%CI = 3.07-9.73); the pooled negative LR − was 0.26 (95%CI = 0.12-0.55) (Fig. 4). The pooled DOR of UE was 21.00 (95% CI = 6.14-71.78) (Fig. 5). The area under the summary receiver operating characteristic curve was 0.89 (SE = 0.0378) (Fig. 6). As a result of the meta regression analysis, it was confirmed that there was no element which could explain the potential source of heterogeneity (Table 2). No evidence of any bias was found (Fig. 7). Egger test also showed no strong statistical evidence to publication bias (t = 0.10, P = .92). The analysis of the Fagan plot showed when the pretest probabilities were 25%, 50%, and 75%; the positive post-test probabilities were 65%, 85%, and 94% while the negative post-test probabilities were 8%, 21%, and 44%, respectively (Fig. 8).

Discussion
TNBC is highly heterogeneous and invasive, and the growth of tumor cells is not regulated by hormones, resulting in a high degree of biological malignancy of cancer cells and a poor prognosis compared with other types of breast cancer. [22] Therefore, early diagnosis and early treatment are of great significance to the prognosis of patients. Due to its benign early imaging features and rapid growth, it is found in the middle and late stages, and there is no targeted treatment due to the lack of effective targets, which has always been a difficult problem in clinical practice. [23] In recent years, with the improvement of the resolution of ultrasound instruments and the diversification of imaging modes, the exploration of breast imaging has been continuously improved.
In traditional 2-dimensional ultrasound, the common ultrasonic manifestations of TNBC are the maximum diameter > 2 cm, clear boundary, smooth edge, lobule, low echo, and posterior echo enhancement and microcalcification. [24] It needs to be differentiated from non-TNBC and easily confused fibroadenoma. Elastography can provide information about tissue hardness and has achieved good results in the differentiation of benign and malignant breast masses, which has been recognized by international guidelines. The results of the study on the diagnosis of TNBC show that TNBC and non-TNBC have some common features on conventional ultrasonic images, but UE is helpful to distinguish TNBC and non-TNBC, especially for small oval or circular lesions < 1 cm. [13] However, for TNBC Table 2 Meta-regression analyses of potential source of heterogeneity 95%CI = 95 % confidence interval, LL = lower limit, RDOR = relative diagnostic odds ratio, SE = standard error, UL = upper limit. Figure 7. Begger funnel plot of publication bias on the pooled OR. In this meta analysis, no announcement bias was found. www.md-journal.com randomly included, the current research results are not consistent. Therefore, this study aimed to provide a comprehensive and reliable conclusion regarding the diagnostic value of UE in the differential diagnosis of TNBC and non-TNBC.
In the present meta-analysis, we systematically evaluated the technical performance and accuracy of UE in the differential diagnosis of TNBC and non-TNBC. Nine independent studies were included, and 317 TNBCs and 1055 non-TNBCs were assessed. The pooled Sen, Spe, and DOR of UE for the diagnosis of TNBCs were 0.78, 0.86, and 21.00, respectively. These results were consistent with the potentially high diagnostic accuracy of UE for TNBCs, because UE can objectively provide the hardness information of the tumor. The threshold effect is usually interpreted as a sudden and radical change in a phenomenon that often occurs after surpassing the quantitative limit. Our findings showed no significant relationship between Sen and Spe within these studies, providing no evidence of a threshold effect. Furthermore, our results showed no direct evidence of publication bias. Collectively, our findings strongly suggest that UE is a highly accurate and noninvasive tool for the qualitative diagnosis of TNBC.
Despite the demonstrated diagnostic accuracy of UE for TNBCs, our study had certain limitations. First, owing to the relatively small sample sizes and low quality of the included studies, there was insufficient data to assess the accuracy of UE. Moreover, the inclusion of studies with histological confirmation only and the retrospective nature of the meta-analysis could have led to subject selection bias. Importantly, the majority of the included studies originated from China, which may adversely affect the reliability and validity of our results.
In conclusion, our meta-analysis suggests that UE may have high diagnostic accuracy in distinguishing TNBC and non-TNBC. It can be used as a supplement to ordinary ultrasonography. However, owing to these limitations, further detailed studies are required to confirm the present findings.